Id-1 activation of PI3K/Akt/NFκB signaling pathway and its significance in promoting survival of esophageal cancer cells

Abstract

Inhibitor of differentiation or DNA binding (Id-1) is a helix-loop-helix protein that is over-expressed in many types of cancer including esophageal cancer. This study aims to investigate its effects on the phosphatidylinositol-3-kinase (PI3K)/Akt/nuclear factor kappa B (NFκB) signaling pathway and the significance in protecting esophageal cancer cells against apoptosis. We found elevated expression of phosphorylated forms of Akt, glycogen synthase kinase 3β and inhibitor of kappa B, as well as increased nuclear translocation of NFκB subunit p65 and NFκB DNA-binding activity, in esophageal cancer cells with stable ectopic Id-1 expression. Transient transfection of Id-1 into HEK293 cells confirmed activation of PI3K/Akt/ NFκB signaling and the effects were counteracted by the PI3K inhibitor LY294002. Treatment with tumor necrosis factor-α (TNF-α) elicited a significantly weaker apoptotic response, following a marked and sustained activation of Akt and NFκB in the Id-1-over-expressing cells, compared with the vector control. The effects of Id-1 on the PI3K/Akt/NFκB signaling pathway and apoptosis were reversed in esophageal cancer cells transfected with siRNA against Id-1. In addition, inhibition of PI3K or NFκB signaling using the PI3K inhibitor LY294002 or the NFκB inhibitor Bay11-7082 increased the sensitivity of Id-1-over-expressing esophageal cancer cells to TNF-α-induced apoptosis. Our results provide the first evidence that Id-1 induces the activation of PI3K/Akt/NFκB signaling pathway, and protects esophageal cancer cells from TNF-α-induced apoptosis in vitro. Inactivation of Id-1 may provide us with a novel strategy to improve the treatment and survival of patients with esophageal cancer. © The Author 2007. Published by Oxford University Press. All rights reserved.